EP1245678B1 - Recombinant proteins of viruses associated with lymphadenopathy syndrome and/or acquired immune deficiency syndrome - Google Patents

Recombinant proteins of viruses associated with lymphadenopathy syndrome and/or acquired immune deficiency syndrome Download PDF

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EP1245678B1
EP1245678B1 EP02077411A EP02077411A EP1245678B1 EP 1245678 B1 EP1245678 B1 EP 1245678B1 EP 02077411 A EP02077411 A EP 02077411A EP 02077411 A EP02077411 A EP 02077411A EP 1245678 B1 EP1245678 B1 EP 1245678B1
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Prior art keywords
arv
sequence
fragment
dna
atcc
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English (en)
French (fr)
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EP1245678A3 (en
EP1245678A2 (en
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Paul A. Luciw
Dino Dina
Kathelyn Steimer
Ray Sanchez Pescador
Carlos George-Nascimento
Deborah Parkes
Rob Hallewell
Philip J. Barr
Martha Truett
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Novartis Vaccines and Diagnostics Inc
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Chiron Corp
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Definitions

  • This invention is in the field of genetic engineering. More particularly, it relates to recombinant viral proteins associated with lymphadenopathy syndrome and/or acquired immune deficiency syndrome.
  • HTLV-I human T-cell lymphotropic virus-I
  • T-cell leukemia viruses A general discussion of the T-cell leukemia viruses may be found in Marx, Science (1984) 224:475-477. Levy, et al. Science (1984) 225 :840-842 report the isolation of ARV (AIDS-associated retroviruses).
  • hTLR human T-cell lymphotropic retrovirus
  • the hTLRs may be shown to be of the same class by being similar in their morphology, serology, reverse transcriptase optima and cytopathology, as identified in the above references.
  • the reverse transcriptase prefers Mg +2 , and has a pH optima of about 7.8.
  • DNA clones containing HTLV-III sequences are disclosed in EP-A-0 173 529 and EP-A-0 185 444.
  • DNA clones containing LAV sequences are disclosed in EP-A-0 178 978 and WO 86/02 383.
  • hTLR DNA sequences that encode hTLR proteins recombinant expression vectors containing such sequences, recombinant hTLR polypeptides, and diagnostic assay using such polypeptides are provided.
  • the hTLR DNA sequences may be used for expression of polypeptides which may be a precursor protein subject to further manipulation by cleavage, or a complete mature protein or fragment thereof.
  • the smallest sequence of interest so as to provide a sequence encoding an amino acid sequence capable of specific binding to a receptor, e.g., an immunoglobulin, will be 21 bp, usually at least 45 bp, exclusive of the initiation codon.
  • the sequence may code for any greater portion of or the complete polypeptide, or may include flanking regions of a precursor polypeptide, so as to include portions of sequences or entire sequences coding for two or more different mature polypeptides.
  • the sequence will usually be less than about 5 kbp, more usually less than about 3 kbp.
  • Sequences of particular interest having open reading frames define the structural genes for the gag proteins (p16 and p25), the env protein, and the pol protein (p31). It is to be understood that the above sequences may be spliced to other sequences present in the retrovirus, so that the 5'-end of the sequence may not code for the N-terminal amino acid of the expression product.
  • the splice site may be at the 5'-terminus of the open reading frame or internal to the open reading frame.
  • the initiation codon for the protein may not be the first codon for methionine, but may be the second or third methionine, so that employing the entire sequence indicated above may result in an extended protein.
  • the gag and env genes there will be proteolytic processing in mammalian cells, which processing may include the removal of extra amino acids.
  • the provirus may be digested with restriction endonucleases, the fragments electrophoresed and fragments having the proper size and duplexing with a probe, when available, are isolated, cloned in a cloning vector, and excised from the vector. The fragments may then be manipulated for expression. Superfluous nucleotides may be removed from one or both termini using Ba131 digestion. By restriction mapping convenient restriction sites may be located external or internal to the coding region.
  • Primer repair or in vitro mutagenesis may be employed for defining a terminus, for insertions, deletion, point or multiple mutations, or the like, where codons may be changed, either cryptic or changing the amino acid, restriction sites introduced or removed, or the like.
  • the lost nucleotides may be replaced using an adaptor. Adaptors are particularly useful for joining coding regions to ensure the proper reading frame.
  • the env domain of the hTLR genome can be obtained by digestion of the provirus with Eco RI and Kpn I and purification of a 3300 base pair (bp) fragment, which fragment contains about 400 bp of 5' non-coding and about 200 bp of 3' non-coding region.
  • Three different methionines coded for by the sequence in the 5' end of the open reading frame may serve as translational initiation sites.
  • Digestion of proviral sequences with Sac I and Eco RV provides a fragment of about 2300 bp which contains the gag domain and a second small open reading frame towards the 3' end of the gag region.
  • the gag domain is about 1500 bp and codes for a large precursor protein which is processed to yield proteins of about 25,000 (p25), 16,000 (p16) and 12,000 (p12) daltons.
  • Digestion with Sac I and Bgl II may also be used to obtain exclusively the gag domain with p12, p25 and partial p16 regions. '
  • Digestion of the provirus with Kpn I and Sst I provides a fragment containing the portion of the pol domain that encodes p31.
  • polypeptides which are expressed by the above DNA sequences may find use in a variety of ways.
  • the polypeptides or immunologically active fragments thereof may find use as diagnostic reagents, being used in labeled or unlabeled form or immobilized (i.e., bound to a solid surface), as vaccines, in the production of monoclonal antibodies. e.g., inhibiting antibodies, or the like.
  • virus can be pelleted from the supernatant of an infected host cell.
  • a 9 kb RNA species is purified by electrophoresis of the viral RNA in low-melting agarose gels, followed by phenol extraction.
  • the purified RNA may then be used as a template with random primers in a reverse transcriptase reaction.
  • the resulting cDNA is then screened for hybridization to polyA+ RNA from infected and uninfected cells. Hybridization occurring from infected, but not uninfected cells, is related to the hTLR.
  • Genomic DNA from infected cells can be restriction enzyme digested and used to prepare a bacteriophage library. Based upon restriction analysis of the previously obtained fragments of the retrovirus, the viral genome can be partially digested with Eco RI and 9 kb-15 kb DNA fragments isolated and employed to prepare the library. The resulting recombinant phage may be screened using a double-lift screening method employing the viral cDNA probe, followed by further purification, e.g., plaque-purification and propagation in large liquid cultures. From the library, the complete sequence of the virus can be obtained and detected with the previously described probe.
  • hLTR DNA (either provirus or cDNA) may be cloned in any convenient vector.
  • Constructs can be prepared, either circular or linear, where the hTLR DNA, either the entire hTLR or fragments thereof, may be ligated to a replication system functional in a microorganism host, either prokaryotic or eukaryotic cells (mammalian, yeast, arthropod, plant).
  • Microorganism hosts include E. coli , B. subtilis, P. aerugenosa , S. cerevisiae , N. crassa , etc.
  • Replication systems may be derived from ColE1, 2 m ⁇ plasmid, ⁇ , SV40, bovine papilloma virus, or the like, that is, both plasmids and viruses.
  • the construct will usually also include one or more markers, which allow for selection of transformed or transfected hosts. Markers may include biocide resistance, e.g., resistance to antibiotics, heavy metals, etc., complementation in an auxotrophic host to provide prototrophy, and the like.
  • expression vectors will be employed.
  • the expression vector may differ from the cloning vector in having transcriptional and translational initiation and termination regulatory signal sequences and may or may not include a replication system which is functional in the expression host.
  • the coding sequence is inserted between the initiation and termination regulatory signals so as to be under their regulatory control.
  • Expression vectors may also include the use of regulatable promoters, e.g., temperature-sensitive or inducible by chemicals, or genes which will allow for integration and amplification of the vector and hTLR DNA such as tk, dhfr, metallothionein, or the like.
  • the expression vector is introduced into an appropriate host where the regulatory signals are functional in such host.
  • the expression host is grown in an appropriate nutrient medium, whereby the desired polypeptide is produced and isolated from cells or from the medium when the polypeptide is secreted.
  • the hTLR DNA sequence may be manipulated to provide for expression of the desired polypeptide in proper juxtaposition to the regulatory signals.
  • the polypeptide products can be obtained in substantially pure form, particularly free of debris from human cells, which debris may include such contaminants as proteins, polysaccharides, lipids, nucleic acids, viruses, bacteria, fungi, etc., and combinations thereof. Generally, the polypeptide products will have less than about 0.1, usually less than about 0.01 weight percent, of contaminating materials from the expression host. Depending upon whether the desired polypeptide is produced in the cytoplasm or secreted, the manner of isolation will vary. Where the product is in the cytoplasm, the cells are harvested, lysed, the product extracted and purified, using solvent extraction, chromatography, gel exclusion, electrophoresis, or the like. Where secreted, the desired product will be extracted from the nutrient medium and purified in accordance with the methods described above.
  • the hTLR DNA sequences may be labeled with isotopic or non-isotopic labels or markers and be used as DNA probes to detect the presence of native hTLR nucleotide sequences in samples suspected of containing same.
  • AIDS related virus-2 (ARV-2) purification and preparation of viral RNA .
  • HUT-78 cells infected with ARV-2 (ATCC Accession No. CRL 8597, deposited on August 7, 1984) were obtained from Dr. Jay Levy, University of California, San Francisco. Cultures were grown for two weeks in RPMI medium with 10% fetal calf serum. Cultures were centrifuged at 2 Krpm for 1 hr at 4°C using a SW-28 rotor. The pellet, containing the virus, was resuspended in 10 mM Tris-HCl, pH 7.5 on ice.
  • the resuspended pellet was treated with 10 ⁇ g of DNase (Boehringer-Mannhein) and was layered onto a linear sucrose gradient (15-50% in 10 mM Tris-HCl, pH 7.5, 1 mM EDTA, 20 mM NaCl). The gradient was spun at 34 Krpm for 4 hr at 4°C, in SW-41 rotor. Five 2.5 ml fractions were collected and an aliquot of each was electrophoresed in a 1% agarose. 5 mM methyl mercury hydroxide gel (Bailey and Davidson, Anal Biochem (1976) 70 :75-85) to determine which contained the 9 kb viral RNA.
  • DNase Boehringer-Mannhein
  • the fraction containing the viral RNA was diluted to 10 ml in 10 mM Tris-HCl, pH 7.5, 1 mM EDTA and was centrifuged at 34 Krpm for 2 hr at 4°C. The pellet was resuspended in 20 mM Tris-HCl, pH 7.6, 10 mM EDTA, 0.1% SDS, and 200 ⁇ g/ml proteinase K. Incubation was carried out for 15 min at room temperature. The mixture was extracted with phenol and the aqueous phase was made 400 mM NaCl and precipitated with ethanol. The pellet was resuspended in water and stored at -70°C.
  • a sample was electrophoresed in a low-melting 1% agarose gel containing 5 mM Methyl mercury hydroxide. After electrophoresis, the gel was stained with 0.1% ethidium bromide and nucleic acid bands were visualized under UV light. The region corresponding to 9 kb was cut from the gel and the agarose was melted at 70°C for 2 to 3 min in three volumes of 0.3 M NaCl, 10 mM Tris, pH 7.5. 1 mM EDTA. The mixture was extracted with an equal volume of phenol. The aqueous phase was reextracted with phenol and was precipitated with ethanol. The pellet was washed with cold 95% ethanol, air dried, resuspended in water and stored at -70°C until use. one hundred ml of culture medium yielded 0.5 to 1 ⁇ g of purified RNA.
  • a 32 P-labeled cDNA was made to the gel purified viral RNA using random primers (calf thymus primers) prepared as described in Maniatis, et al, A Laboratory Manual , Cold Spring Harbor, NY, 1982.
  • the reaction mixture contained 2 ⁇ l of 0.5 M MgCl 2 ; 5 ⁇ l of 0.1 M dithiothreitol; 2.5 ⁇ l each of 10 mM dATP, 10 mM dGTP and 10 mM dTTP; 2.5 ⁇ l calf thymus primer (100A 260 /ml); 0.5 ⁇ g viral RNA; 5 ⁇ l of actinomycin D (200 ⁇ g/ml); 10 ⁇ l of 32 P-dCTP (> 3000 Ci/mmole, 1 mCi/ml) and 1 ⁇ l of AMV reverse transcriptase (17 units/ ⁇ l) in a 50 ⁇ l reaction volume.
  • the reaction was incubated for 1 hr at 37°C.
  • the probe was purified away from free nucleotides by gel filtration using a Sephadex G50 column.
  • the void volume was pooled, NaCl was added to a final concentration of 400 mM and carrier single-stranded DNA to 100 ⁇ g/ml, and the cDNA was precipitated with ethanol.
  • the pellet was resuspended in water and incorporated 32 P counts were determined.
  • PolyA+ RNA was prepared from HUT-78 cells infected with ARV-2, ARV-3 or ARV-4 (three different isolates from three different AIDS patients) and from uninfected HUT-78 cells.
  • the polyA+ RNA was electrophoresed on 1% agarose gels containing 5 mM methyl mercury hydroxide (Bailey and Davidson, supra), was transferred to nitrocellulose filters, and hybridized with the homologous probe prepared as described in Section 2. Hybridizations were carried out in 50% formamide, 3 x SSC at 42°C. Washes were at 50°C in 0.2 x SSC. A 9 kbp band was present in all three samples of infected HUT-78 cells. This band was absent in polyA+ from uninfected cells.
  • High molecular weight DNA (chromosomal) was prepared from cultures of HUT-78 cells infected with ARV-2 and from non-infected HUT-78 cells following the procedure of Luciw, et al, Molec and Cell Biol (1984) 4 :1260-1269.
  • the DNA was digested with restriction enzyme(s), electrophoresed in 1% agarose gels and blotted onto nitrocellulose following the procedure described by Southern, (1975), supra.
  • Blots were hybridized with the 32 P-labeled probe (10 6 cpm/blot) in a mixture containing 50% formamide, 3 x SSC, 10 mM Hepes, pH 7.0, 100 ⁇ g/ml denatured carrier DNA, 100 ⁇ g/ml yeast RNA and 1 x Denhardt's for 36 hr at 42°C. Filters were washed once at room temperature in 2 x SSC and twice at 42°C in 0.2 x SSC, 0.1% SDS. Filters were air dried and exposed to X-Omat film using an intensifying screen.
  • the homologous 32 P-probe to ARV-2 hybridized specifically to two bands in the DNA from infected cells restricted with Sac I. These bands were absent when DNA of non-infected cells was used, indicating that the probe is hybridizing specifically to infected cells presumably to the provirus integrated in the chromosomal DNA.
  • the molecular weight of the bands is approximately 5 kb and 3 kb.
  • FIG. 1 shows a schematic map of the positions of restriction enzyme sites in the proviral sequence, and indicates fragment sites.
  • High molecular weight cell DNA from infected HUT-78 cells was prepared following the procedure of Luciw, et al, supra.
  • the DNA was digested with Eco RI, which cuts once in the provirus, centrifuged in a sucrose gradient and fractions corresponding to 8-15 kb were pooled, dialyzed and concentrated by ethanol precipitation.
  • the bacteriophage ⁇ derivative cloning vector was prepared following the procedure of Luciw, et al, supra. The DNA was digested with Eco RI, which cuts once in the provirus, centrifuged in a sucrose gradient and fractions corresponding to 8-15 kb were pooled, dialyzed and concentrated by ethanol precipitation.
  • the bacteriophage ⁇ derivative cloning vector was prepared following the procedure of Luciw, et al, supra.
  • phage DNA was digested with restriction enzymes, electrophoresed on 1% agarose gels, and visualized with ethidium bromide under ultraviolet light. The DNA from these gels was transferred to nitrocellulose and annealed with viral cDNA probe.
  • ⁇ ARV-2(9B) One of the 11 phage, designated ⁇ ARV-2(9B), was deposited at the ATCC on 25 January 1985 and given Accession No. 40158.
  • ⁇ ARV-2(9B) contained an insertion of full-length proviral DNA along with flanking cell sequences. Digestion of ⁇ ARV-2(9B) DNA with Sac I yielded viral DNA fragments of 3.8 kb and 5.7 kb.
  • Eco RI digestion of ⁇ ARV-2(9B) produced virus containing DNA species at 6.4 kb and 8.0 kb; a double digest of Sac I and Eco RI gave viral DNA fragments at 3.8 kb and 5.4 kb. This pattern is consistent with that of a provirus linked to cell DNA.
  • phage was obtained that (1) possessed the left half of the viral genome from the Eco RI site in viral DNA extending into flanking cell DNA ( ⁇ ARV-2(8A)) and (2) phage that had the right half of the viral genome ( ⁇ ARV-2(7D)) from the Eco RI site in viral DNA extending into flanking cell DNA.
  • Bacteriophages ⁇ ARV-2(7D) (right) and ⁇ ARV-2(8A) (left) were deposited at the ATCC on October 26, 1984 and given Accession Nos. 40143 and 40144, respectively.
  • restriction enzyme digests of DNA from HUT-78 cells infected with ARV-3 and ARV-4 were analyzed with the probe made from cloned ARV-2 DNA.
  • the Sac I digest of ARV-3 DNA was similar to that of ARV-2 whereas the Hin dIII digests displayed different patterns.
  • the Sac I digest and the Pst I digest of ARV-4 DNA differed from the corresponding digests of ARV-2 DNA.
  • the intensity of the annealing signals obtained with ARV-3 and ARV-4 samples was much lower (about 10-fold less) than that for ARV-2 DNA probably as a result of the fact that fewer cells were infected in the ARV-3 and ARV-4 cultures.
  • the viral-specific DNA fragments produced by Sac I treatment of ARV-3 and ARV-4 DNA totaled 9.0-9.5 kbp, a value similar to that of ARV-2 and in consonance with the RNA genome sizes.
  • Fragments or subfragments of ARV-2 DNA from ⁇ phage 9B were prepared and cloned into M13 according to conventional procedures (Maniatis, et al, supra). Sequencing was performed according to Sanger, et al, Proc Natl Acad Sci USA (1977) 74 :5463, using the universal M13 primer or chemically synthesized primers complementary to ARV-2 sequence. The sequence is shown in Figure 2.
  • a partial env protein is synthesized by S. cerevisiae 2150-2-3 transformed with plasmid pDPC303.
  • Plasmid pDPC303 is a yeast expression vector which contains the sequence coding for 2/3 of the env protein as well as pBR322, sequences including the amp R gene and 2-micron sequences including the yeast leu 2-04 gene. Expression of env is under regulation of the yeast pyruvate kinase promoter and terminator sequences.
  • Yeast strain S. cerevisiae 2150-2-3 has the following genotype: Mat a, ade 1, leu 2-112, cir°. This strain was obtained from Dr. Leland Hartwell, University of Washington.
  • Plasmid pDPC303 contains an "expression cassette" (described below) for env cloned into the Bam HI site of vector pCl/l.
  • Vector pCl/l contains pBR322 and 2 micron sequences including the amp R and yeast leu 2-04 markers. It was derived from pJDB219d (Beggs. Nature (1978), 275 : 104) by replacing the pMB9 region with pBR322 sequences.
  • the "expression cassette" for env consists of the following sequences fused together in this order (5' to 3'): yeast pyruvate kinase (PYK) promoter, env cDNA, and PYK terminator.
  • PYK yeast pyruvate kinase
  • env cDNA env cDNA
  • PYK terminator The PYK promoter and terminator regions were derived from PYK cDNA isolated as described in Burke, et al, J Biol Chem (1983) 258 :2193-2201.
  • the env fragment cloned into the expression cassette was derived from ARV-2 cDNA and comprises a 1395 bp cDNA fragment which codes for env amino acid residues coded by nt 5857 to nt 7251 ( Figure 2).
  • Figure 7 shows the coding strand of the nucleotide sequence cloned in pDPC303 and the amino acid sequence derived from it.
  • DNA sequences that are not underlined in the figure were derived directly from the ARV-2 (9B) cDNA described above. All other sequences were either chemically synthesized or derived from the PYK vector.
  • Yeast cells S. cerevisiae 2150-2-3 ( Mat a, ade 1 , leu 2-04 , cir °) were transformed as described by Hinnen et al ( PNAS (1978) 75 :1929-1933) and plated onto leu- selective plates. Single colonies were inoculated into leu- selective media and grown to saturation. Cells were harvested and the env protein was purified and characterized as described below.
  • Frozen S. cerevisiae 2150-2-3 (pDPC303) are thawed and suspended in 1 volume of lysis buffer (1 ⁇ g/ml pepstatin. 0.001 M PMSF. 0.001 M EDTA, 0.15 M NaCl, 0.05 M Tris-HCl pH 8.0), and 1 volume of acid-washed glass beads are added.
  • Cells are broken in a non-continuous system using a 300 ml glass unit of Dyno Mill at 3000 rpm for 10 min. The jacket is kept cool by a -20°C ethylene glycol solution. Glass beads are decanted by letting the mixture set for 3 minutes on ice. The cell extract is recovered and centrifuged at 18,000 rpm (39.200 x g) for 35 min. The supernatant is discarded and the precipitate (pellet 1) is further treated as indicated below.
  • Pellet 1 is resuspended in 4 volumes of Tris-HCl buffer (0.01 M Tris-HCl, pH 8.0, 0.01 M NaCl, 0.001 M PMSF, 1 ⁇ g/ml pepstatin, 0.001 M EDTA, 0.1% SDS) and extracted for 2 hr at 4°C with agitation. The solution is centrifuged at 6,300 x g for 15 min.
  • Tris-HCl buffer 0.01 M Tris-HCl, pH 8.0, 0.01 M NaCl, 0.001 M PMSF, 1 ⁇ g/ml pepstatin, 0.001 M EDTA, 0.1% SDS
  • pellet 2 The insoluble fraction (pellet 2) is resuspended in 4 volumes (360 ml) of PBS (per liter: :0.2 g KCl, 0.2 g KH 2 PO 4 , 8.0 g NaCl, 2.9 g Na 2 HPO 4 .12H 2 O), 0.1% SDS, 0.001 M EDTA, 0.001 M PMSF, 1 ⁇ g/ml pepstatin, and centrifuged at 6,300 x g for 15 min.
  • the pellet (pellet 3) is suspended in 4 volumes of PBS, 0.2% SDS. 0.001 M EDTA.
  • the soluble fraction is concentrated by precipitation with 30% ammonium sulfate at 4°C.
  • the pellet (pellet 4) is resuspended in 2.3% SDS, 5% ⁇ -mercaptoethanol, and chromatographed on an ACA 34 (LKB Products) gel filtration column. The column is equilibrated with PBS, 0.1% SDS, at room temperature. Chromatography is developed in the same solution with a flow rate of 0.3 ml/min. Five ml fractions are collected, pooled and characterized by protein gel electrophoresis, Western analysis, and ELISA. If needed, pooled fractions are concentrated by vacuum dialysis on Spectrapor #2 (MW cutoff 12-14K).
  • SDS polyacrylamide gel analysis (12% acrylamide gels) showed that a new 55,000 dalton protein was being synthesized in yeast cells transformed with the env-containing vector.
  • the 55,000 dalton protein is absent from cells transformed with control plasmid (vector without env insert).
  • the identity of env was confirmed by both ELISA (see 9.E.4.c) and Western analysis using AIDS patient serum. In both assays the 55,000 dalton protein showed immunoreactivity. No reactivity was obtained with serum from a normal individual.
  • Recombinant env was also expressed in mammalian (Cos) cells.

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